Neurological and neurodegenerative diseases and disorders represent potentially debilitating conditions and can affect people of all ages. Neurological and neurodegenerative diseases and disorders may be acquired, congenital, hereditary or sporadic conditions. They are typically associated with widely varying degrees of difficulty which may have significant mental, emotional, physical, and economic consequences for individuals.
Neurodegenerative diseases and disorders are typically characterized by progressive nervous system dysfunction and may be associated with atrophy of the affected central or peripheral structures of the nervous system. Examples of neurodegenerative diseases and disorders include but are not limited to dementia, including Alzheimer's Disease, degenerative nerve diseases, encephalitis, epilepsy, hydrocephalus, stroke, Parkinson's disease, multiple sclerosis, brain cancer, cognitive dysfunction syndrome, amyotrophic lateral sclerosis (ALS), and Huntington's disease.
The term “dementia” is often used to refer to a broad category of brain diseases characterised by a progressive decline in cognition and mental ability wherein memory, thinking, and judgement may be impaired. This type of neurodegenerative disease typically affects those over the age of 60, however early onset forms of the disease are also known. It is estimated that approximately 24 million people worldwide suffer from dementia, of which approximately 50 to 70% are estimated to be due to Alzheimer's disease.
Alzheimer's disease is a highly variable condition which presents and develops differently in each individual. While the cause and progression of the disease is not well understood, there are many common symptoms. In the initial stages, sufferers often exhibit short term memory loss. As the disease progresses, symptoms may include confusion, irritability, aggression, mood swings, trouble with language, and long-term memory loss. The later stages are often characterised by loss of bodily functions which ultimately results to death.
Diagnosis of Alzheimer's disease is usually based on an evaluation of behaviour and cognition, however brain scans and examination of brain tissue is required for a definitive diagnosis. Other neurological and neurodegenerative diseases are also associated with dementia-like symptoms. For example, dementia commonly develops in the advanced stages of Parkinson's disease. Furthermore, cognitive dysfunction syndrome has been recognized as having similarities with Alzheimer's disease.
To date, there is no known cure for dementia or Alzheimer's disease. Current treatments include pharmaceutical and psychosocial treatments, however, no single medication or treatment is known to relieve or reverse the core symptoms of Alzheimer's disease with current treatments typically offering a relatively small symptomatic benefit.
A reduction in the activity of the cholinergic neurons is associated with Alzheimer's disease. Administration of acetylcholinesterase inhibitors may thus be used to increase the concentration of acetylcholine in the brain and counter the loss of acetylcholine caused by the death of cholinergic neurons. Current pharmaceutical treatments for the cognitive symptoms associated with Alzheimer's disease thus include acetylcholinesterase inhibitors and NMDA receptor antagonists.
Rivastigmine, an acetylcholinesterase inhibitor, is currently used for the treatment of patients suffering from neurological conditions, such as dementia caused by Alzheimer's disease and Parkinson's disease (Birks et al. 2009; Birks et al. 2015; Maidment et al. 2006). Furthermore, the use of cholinesterase inhibitors has been shown to help improve cholinergic function associated with other disorders, including cognitive dysfunction syndrome (Gonzalez-Martinez A. et al. 2013; Araujo J A. et al. 2011).
Rivastigmine has the following structure, and may also be provided as a pharmaceutically acceptable salt or hydrate:

Currently, rivastigmine is available as a capsule or a solution for oral administration and as a transdermal patch. However, the orally available forms of rivastigmine are associated with significant side effects, including nausea, vomiting, diarrhoea and asthenia (Feldman and Lane 2007; Winblad et al. 2007). Additionally, oral rivastigmine has low absolute oral bioavailability of about 35% at a dose of 3 mg, and at higher oral doses of 6 mg and above it exhibits non-linear oral pharmacokinetics (Hossain et al. 2002). The effective treatment of Alzheimer's disease ideally requires central cholinesterase inhibition in order to improve cholinergic signalling in the brain (Cutler et al. 1998; Gobburu et al. 2001). However, greater peripheral cholinesterase inhibition may also occur where higher doses of a given drug are administered to counter low bioavailability, as is the case with oral rivastigmine. This may in turn result in a higher risk of adverse events and associated unwanted side effects.
While the rivastigmine transdermal patch addresses some of these deficiencies, it is known to cause skin irritation in a significant proportion of patients and may also disturb circadian rhythms resulting in disrupted sleep patterns (Lamer 2010; Grossberg et al. 2010; Kurz et al. 2009). Consequently, the treatment discontinuation rate for the transdermal patch was found to be higher than the oral capsule (Winblad et al. 2007).
Accordingly, there is an on-going need to develop new methods of treating neurodegenerative diseases and disorders, such as Alzheimer's disease.